C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use

ABSTRACT

In its many embodiments, the present invention provides certain C5-spiro iminothiadiazine dioxide compounds, including compounds Formula (I): (structurally represented) or tautomers thereof, and pharmaceutically acceptable salts of said compounds, wherein R1, R2, R3, X, Y, s, ring A, RA, m, -L1-, and RL are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer&#39;s disease, are also disclosed.

FIELD OF THE INVENTION

This invention provides certain C5-spiro iminothiadiazine dioxidecompounds, and compositions comprising these compounds, as inhibitors ofBACE, which may be useful for treating or preventing pathologies relatedthereto.

BACKGROUND

Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrilsand plaques, which are regarded as having a role in an increasing numberof pathologies. Examples of such pathologies include, but are notlimited to, Alzheimer's disease, Down's syndrome, Parkinson's disease,memory loss (including memory loss associated with Alzheimer's diseaseand Parkinson's disease), attention deficit symptoms (includingattention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and Down's syndrome), dementia (includingpre-senile dementia, senile dementia, dementia associated withAlzheimer's disease, Parkinson's disease, and Down's syndrome),progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment (including olfactory impairmentassociated with Alzheimer's disease, Parkinson's disease, and Down'ssyndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy),hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”),glaucoma, amyloidosis, type II diabetes, hemodialysis (β2 microglobulinsand complications arising therefrom), neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease,traumatic brain injury and the like.

Aβ peptides are short peptides which are made from the proteolyticbreak-down of the transmembrane protein called amyloid precursor protein(“APP”). Aβ peptides are made from the cleavage of APP by β-secretaseactivity at a position near the N-terminus of Aβ, and by gamma-secretaseactivity at a position near the C-terminus of Aβ. (APP is also cleavedby α-secretase activity, resulting in the secreted, non-amyloidogenicfragment known as soluble APPα.) Beta site APP Cleaving Enzyme(“BACE-1”) is regarded as the primary aspartyl protease responsible forthe production of Aβ by β-secretase activity. The inhibition of BACE-1has been shown to inhibit the production of Aβ.

AD is estimated to afflict more than 20 million people worldwide and isbelieved to be the most common cause of dementia. AD is a diseasecharacterized by degeneration and loss of neurons and also by theformation of senile plaques and neurofibrillary tangles. Presently,treatment of Alzheimer's disease is limited to the treatment of itssymptoms rather than the underlying causes. Symptom-improving agentsapproved for this purpose include, for example, N-methyl-D-aspartatereceptor antagonists such as memantine (Namenda®, ForestPharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil(Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine(Razadyne Reminyl®), and tacrine (Cognex®).

In AD, Aβ peptides, formed through β-secretase and gamma-secretaseactivity, can form tertiary structures that aggregate to form amyloidfibrils. Aβ peptides have also been shown to form Aβ oligomers(sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβoligomers are small multimeric structures composed of 2 to 12 Aβpeptides that are structurally distinct from Aβ fibrils. Amyloid fibrilscan deposit outside neurons in dense formations known as senile plaques,neuritic plaques, or diffuse plaques in regions of the brain importantto memory and cognition. Aβ oligomers are cytotoxic when injected in thebrains of rats or in cell culture. This Aβ plaque formation anddeposition and/or Aβ oligomer formation, and the resultant neuronaldeath and cognitive impairment, are among the hallmarks of ADpathophysiology. Other hallmarks of AD pathophysiology includeintracellular neurofibrillary tangles comprised of abnormallyphosphorylated tau protein, and neuroinflammation.

Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/orplaque play a causal role in AD pathophysiology. (Ohno et al.,Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genesfor APP and presenilins 1/2 (PS1/2) are known to cause familial AD andan increase in the production of the 42-amino acid form of Aβ isregarded as causative. Aβ has been shown to be neurotoxic in culture andin vivo. For example, when injected into the brains of aged primates,fibrillar Aβ causes neuronal cell death around the injection site. Otherdirect and circumstantial evidence of the role of Aβ in Alzheimeretiology has also been published.

BACE-1 has become an accepted therapeutic target for the treatment ofAlzheimer's disease. For example, McConlogue et al., J. Bio. Chem., Vol.282, No. 36 (September 2007), have shown that partial reductions ofBACE-1 enzyme activity and concomitant reductions of Aβ levels lead to adramatic inhibition of Aβ-driven AD-like pathology, making β-secretase atarget for therapeutic intervention in AD. Ohno et al. Neurobiology ofDisease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1in 5×FAD mice abrogates Aβ generation, blocks amyloid deposition,prevents neuron loss found in the cerebral cortex and subiculum (brainregions manifesting the most severe amyloidosis in 5×FAD mice), andrescues memory deficits in 5×FAD mice. The group also reports that Aβ isultimately responsible for neuron death in AD and concludes that BACE-1inhibition has been validated as an approach for the treatment of AD.Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324,established that inhibition or loss of β-secretase activity produces noprofound phenotypic defects while inducing a concomitant reduction inAβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, reportthat mice deficient in BACE-1 have normal phenotype and abolishedβ-amyloid generation.

More recently, Jonsson, et al. have reported in Nature, Vol. 488, pp.96-99 (August 2012), that a coding mutation (A673T) in the APP geneprotects against Alzheimer's disease and cognitive decline in theelderly without Alzheimer's disease. More specifically, the A allele ofrs63750847, a single nucleotide polymorphism (SNP), results in analanine to threonine substitution at position 673 in APP (A673T). ThisSNP was found to be significantly more common in a healthy elderlycontrol group than in an Alzheimer's disease group. The A673Tsubstitution is adjacent to the aspartyl protease beta-site in APP, andresults in an approximately 40% reduction in the formation ofamyloidogenic peptides in a heterologous cell expression system invitro. Jonsson, et al. report that an APP-derived peptide substratecontaining the A673T mutation is processed 50% less efficiently bypurified human BACE1 enzyme when compared to a wild-type peptide.Jonsson et al. indicate that the strong protective effect of theAPP-A673T substitution against Alzheimer's disease provides proof ofprinciple for the hypothesis that reducing the beta-cleavage of APP mayprotect against the disease.

BACE-1 has also been identified or implicated as a therapeutic targetfor a number of other diverse pathologies in which Aβ or Aβ fragmentshave been identified to play a causative role. One such example is inthe treatment of AD-type symptoms of patients with Down's syndrome. Thegene encoding APP is found on chromosome 21, which is also thechromosome found as an extra copy in Down's syndrome. Down's syndromepatients tend to acquire AD at an early age, with almost all those over40 years of age showing Alzheimer's-type pathology. This is thought tobe due to the extra copy of the APP gene found in these patients, whichleads to overexpression of APP and therefore to increased levels of Aβcausing the prevalence of AD seen in this population. Furthermore,Down's patients who have a duplication of a small region of chromosome21 that does not include the APP gene do not develop AD pathology. Thus,it is thought that inhibitors of BACE-1 could be useful in reducingAlzheimer's type pathology in Down's syndrome patients.

Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol.104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eyeand a major cause of irreversible blindness worldwide. Guo et al. reportthat Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) inexperimental glaucoma and induces significant RGC cell loss in vivo in adose- and time-dependent manner. The group report having demonstratedthat targeting different components of the Aβ formation and aggregationpathway, including inhibition of β-secretase alone and together withother approaches, can effectively reduce glaucomatous RGC apoptosis invivo. Thus, the reduction of Aβ production by the inhibition of BACE-1could be useful, alone or in combination with other approaches, for thetreatment of glaucoma.

Another example is in the treatment of olfactory impairment. Getchell etal., Neurobiology of Aging, 24 (2003), 663-673, have observed that theolfactory epithelium, a neuroepithelium that lines the posterior-dorsalregion of the nasal cavity, exhibits many of the same pathologicalchanges found in the brains of AD patients, including deposits of Aβ,the presence of hyperphosphorylated tau protein, and dystrophic neuritesamong others. Other evidence in this connection has been reported byBacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin JA, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; DaviesD C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am JPsychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull,1987; 18:597-600. It is reasonable to suggest that addressing suchchanges by reduction of Aβ by inhibition of BACE-1 could help to restoreolfactory sensitivity in patients with AD.

For compounds which are inhibitors of BACE-2, another example is in thetreatment of type-II diabetes, including diabetes associated withamyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2immunoreactivity has been reported in secretory granules of beta cells,co-stored with insulin and IAPP, but lacking in the other endocrine andexocrine cell types. Stoffel et al., WO2010/063718, disclose the use ofBACE-2 inhibitors in the treatment of metabolic diseases such as Type-IIdiabetes. The presence of BACE-2 in secretory granules of beta cellssuggests that it may play a role in diabetes-associated amyloidogenesis.(Finzi, G. Franzi, et al., Ultrastruct Pathol. 2008 November-December;32(6):246-51.)

Other diverse pathologies characterized by the formation and depositionof Aβ or fragments thereof, and/or by the presence of amyloid fibrils,oligomers, and/or plaques, include neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”),Creutzfeld-Jakob disease and the like, type II diabetes (which ischaracterized by the localized accumulation of cytotoxic amyloid fibrilsin the insulin producing cells of the pancreas), and amyloid angiopathy.In this regard reference can be made to the patent literature. Forexample, Kong et al., US2008/0015180, disclose methods and compositionsfor treating amyloidosis with agents that inhibit Aβ peptide formation.As another example, Loane, et al. report the targeting of amyloidprecursor protein secretases as therapeutic targets for traumatic braininjury. (Loane et al., “Amyloid precursor protein secretases astherapeutic targets for traumatic brain injury”, Nature Medicine,Advance Online Publication, published online Mar. 15, 2009.) Still otherdiverse pathologies characterized by the inappropriate formation anddeposition of Aβ or fragments thereof, and/or by the presence of amyloidfibrils, and/or for which inhibitor(s) of BACE-1 is expected to be oftherapeutic value are discussed further hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides certain C5-spiro iminothiadiazine dioxidecompounds, which are collectively or individually referred to herein as“compound(s) of the invention,” as described herein. The compounds ofthe invention are useful as inhibitors of BACE-1 and/or BACE-2.

In one embodiment, the compounds of the invention have the structuralFormula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of H, alkyl, heteroalkyl,cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, and -alkyl-cycloalkyl, is optionally substituted with one ormore halogen;

R² is selected from the group consisting of H, halogen, alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substitutedwith one or more halogen;

R³ is selected from the group consisting of H, halogen, alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substitutedwith one or more halogen;

s is 0 or 1;

when s is 0, then Y is absent and X is selected from the groupconsisting of —C(R^(1X))₂—, —O—, —S—, —S(O)—, and —S(O)₂—, and

when s is 1, then X is selected from the group consisting of—C(R^(1X))₂—, —O—, —S—, —S(O)—, and —S(O)₂—, and Y is —C(R^(1Y))₂—,

or, alternatively, when s is 1, then X is —C(R^(1X))₂— and Y is selectedfrom the group consisting of —C(R^(1Y))₂—, —O—, —S—, —S(O)—, and—S(O)₂—;

each R^(1X) (when present) is independently selected from the groupconsisting of: H, halogen, alkyl, heteroalkyl, and cycloalkyl,

-   -   wherein said alkyl, heteroalkyl, and cycloalkyl are each        optionally independently unsubstituted or substituted with one        or more halogen;

each R¹ (when present) is independently selected from the groupconsisting of: H, halogen, alkyl, heteroalkyl, and cycloalkyl,

-   -   wherein said alkyl, heteroalkyl, and cycloalkyl are each        optionally independently unsubstituted or substituted with one        or more halogen;

ring A is selected from the group consisting of aryl and heteroaryl;

m is 0 or more;

each R^(A) (when present) is independently selected from the groupconsisting of: halogen, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5A))₃,—N(R^(6A))₂, —OR^(6A), —SR^(6A), alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl,

-   -   wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl        of R^(A) are each optionally independently unsubstituted or        substituted with one or more groups independently selected from        R⁸;

n is 0 or 1;

-L₁- represents a bond or a divalent moiety selected from the groupconsisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-,—NHC(O)—, —C(O)NH—, —C(S)NH—, —NHC(S)—, —NH—, —NHS(O)₂—, —S(O)₂NH—,—O—CH₂—, —CH₂—O—, —NHCH₂—, and —CH₂NH—;

R^(L) is selected from the group consisting of alkyl and heteroalkyl,wherein said alkyl and heteroalkyl of R^(L) are each optionallyunsubstituted or substituted with one or more halogen;

or, alternatively, R^(L) is a moiety having the formula

wherein q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of lower alkyl and lower heteroalkyl, wherein each said loweralkyl and lower heteroalkyl is optionally substituted with one or morehalogen;

ring B is selected from the group consisting of aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;

p is 0 or more; and

each R^(B) (when present) is independently selected from the groupconsisting of: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃,—N(R^(6B))₂, —NR^(7B)C(O)R^(6B), —NR⁷S(O)₂R^(6B),—NR^(7B)S(O)₂N(R^(6B))₂, —NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B),—C(O)R^(6B), —C(O)OR^(6B), —C(O)N(R^(6B))₂, —S(O)R^(6B), —S(O)₂R^(6B),—S(O)₂N(R^(6B))₂, —OR^(6B), —SR^(6B), alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

-   -   wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,        aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(B)        are each optionally independently unsubstituted or substituted        with one or more groups independently selected from R⁹;

each R^(5X), R^(5Y), R^(5A), R^(5B), and R^(5C) (when present) isindependently selected from the group consisting of alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl,

-   -   wherein each said alkyl, heteroalkyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of        R^(5X), R^(5Y), R^(5A), R^(5B), and R^(5C) is unsubstituted or        substituted with one or more halogen;

each R^(6X), R^(6Y), R^(6A) and R^(6C) (when present) is independentlyselected from the group consisting of H, alkyl, -alkyl-OH, alkenyl,alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl,

wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl of R^(6X), R^(6Y), R^(6A) and R^(6C) is unsubstitutedor substituted with one or more groups independently selected fromhalogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy,heteroalkoxy, and haloalkoxy;

each R^(6B) (when present) is independently selected from the groupconsisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

-   -   wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl,        heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,        heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,        heteroaryl, and -alkyl-heteroaryl of R^(6B) is unsubstituted or        substituted with one or more groups independently selected from        halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy,        heteroalkoxy, and haloalkoxy;

each R^(7X), R^(7Y), R^(7A), R^(7B), and R^(7C) (when present) isindependently selected from the group consisting of H, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl,

-   -   wherein each said alkyl, heteroalkyl, -heteroalkyl-OH,        cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and        -alkyl-heterocycloalkyl of R^(7X), R^(7Y), R^(7A), R^(7B), and        R^(7C) is unsubstituted or substituted with one or more halogen;

each R⁸ (when present) is independently selected from the groupconsisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy,lower cycloalkyl, and lower heterocycloalkyl, wherein each said loweralkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lowerheterocycloalkyl of R⁸ is optionally substituted with halogen; and

each R⁹ (when present) is independently selected from the groupconsisting of halogen, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.

In other embodiments, the invention provides compositions, includingpharmaceutical compositions, comprising one or more compounds of theinvention (e.g., one compound of the invention), or a tautomer thereof,or a pharmaceutically acceptable salt or solvate of said compound(s)and/or said tautomer(s), optionally together with one or more additionaltherapeutic agents, optionally in an acceptable (e.g., pharmaceuticallyacceptable) carrier or diluent.

In other embodiments, the invention provides various methods oftreating, preventing, ameliorating, and/or delaying the onset of an Aβpathology and/or a symptom or symptoms thereof, comprising administeringa composition comprising an effective amount of one or more compounds ofthe invention, or a tautomer thereof, or pharmaceutically acceptablesalt or solvate of said compound(s) and/or said tautomer(s), to apatient in need thereof. Such methods optionally additionally compriseadministering an effective amount of one or more additional therapeuticagents, simultaneously or sequentially, suitable for treating thepatient being treated.

These and other embodiments of the invention, which are described indetail below or will become readily apparent to those of ordinary skillin the art, are included within the scope of the invention.

DETAILED DESCRIPTION

For each of the following embodiments, any variable not explicitlydefined in the embodiment is as defined in Formula (I) or (IA). In eachof the embodiments described herein, each variable is selectedindependently of the other unless otherwise noted.

In one embodiment, the compounds of the invention have the structuralFormula (IA):

or a tautomer thereof having the structural Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined in Formula (I).

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is selected from the group consisting of H, methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, and —CH₂CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is selected from the group consisting of H, fluoro, methyl, ethyl,propyl, butyl, cyclopropyl, —CH₂-cyclopropyl, and —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R³ is selected from the group consisting of H, fluoro, methyl, ethyl,propyl, butyl, cyclopropyl, —CH₂-cyclopropyl, and —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R³ is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R³ is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is selected from the group consisting of of H, fluoro, methyl, ethyl,propyl, butyl, cyclopropyl, —CH₂-cyclopropyl, and —CH₂OCH₃; and R³ is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is selected from the group consisting of H and methyl; and R³ is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R² is H; and R³ is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is methyl; R² is H; and R³ is H.

In some embodiments, s is 0 and Y is absent. In these embodiments, themoiety:

has the formula:

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

s is 0;

Y is absent; and

X is selected from the group consisting of —C(R^(1X))₂— and —O—,

wherein each R^(1X) (when present) is independently selected from thegroup consisting of H, halogen, lower alkyl, and lower heteroalkyl,wherein said lower alkyl and lower heteroalkyl are each optionallyindependently unsubstituted or substituted with one or more halogen.

In an alternative of the immediately preceding embodiment, each R^(1X)(when present) is independently selected from the group consisting of H,fluoro, methyl, ethyl, —CF₃, —CHF₂, and —CH₂F.

In another alternative of the immediately preceding embodiment, eachR^(1X) (when present) is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

s is 1;

X is selected from the group consisting of —C(R^(1X))₂—, and —O—;

Y is —C(R^(1Y))₂—;

R^(1X) (when present) is independently selected from the groupconsisting of H, halogen, lower alkyl, and lower heteroalkyl, whereinsaid lower alkyl and lower heteroalkyl are each optionally independentlyunsubstituted or substituted with one or more halogen; and

R^(1Y) is H.

In an alternative of the immediately preceding embodiment, each R^(1X)(when present) is selected from the group consisting of H, methyl,ethyl, —CF₃, —CHF₂, and —CH₂F.

In another alternative of the immediately preceding embodiment, eachR^(1X) (when present) is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

s is 1;

X is —C(R^(1X))₂—; and

Y is selected from the group consisting of —C(R^(1Y))₂— and —O—;

each R^(1X) is independently selected from the group consisting of H,halogen, lower alkyl, and lower heteroalkyl, wherein said lower alkyland lower heteroalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen; and each R¹ (when present) is H.

In an alternative of the immediately preceding embodiment, each R^(1X)(when present) is selected from the group consisting of H, methyl,ethyl, —CF₃, —CHF₂, and —CH₂F.

In another alternative of the immediately preceding embodiment, eachR^(1X) is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

X is —O—; and

Y is —C(R^(1Y))₂—,

wherein each R^(1Y) is independently selected from the group consistingof H, lower alkyl, and lower heteroalkyl, wherein said lower alkyl andlower heteroalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen.

In an alternative of the immediately preceding embodiment, each R¹ isselected from the group consisting of H, methyl, ethyl, —CF₃, —CHF₂, and—CH₂F.

In another alternative of the immediately preceding embodiment, each R¹is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

X is —C(R^(1X))₂—; and

Y is —O—,

wherein each R^(1X) is independently selected from the group consistingof H, lower alkyl, and lower heteroalkyl, wherein said lower alkyl andlower heteroalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen.

In an alternative of the immediately preceding embodiment, each R^(1X)is selected from the group consisting of H, methyl, ethyl, —CF₃, —CHF₂,and —CH₂F.

In another alternative of the immediately preceding embodiment, eachR^(1X) is H.

The following alternatives of ring A are applicable to any of theembodiments described hereinabove.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, and triazinyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl,pyrimidinyl, pyrazinyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl, andthienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl and pyridyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is phenyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —OCH₃, —CH₂OCH₃, methyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OCH₃, —CH₂OCH₃, methyl, cyclopropyl,—CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, and triazinyl;

m is 0, 1, or 2; and

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl,pyrimidinyl, pyrazinyl, and thienyl;

m is 0 or 1; and

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —OCH₃, —CH₂OCH₃, methyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridyl, andthienyl;

m is 0 or 1; and

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OCH₃, —CH₂OCH₃, methyl, cyclopropyl,—CF₃, —CHF₂, and —CH₂F.

It shall be understood that the phrase “m is 0 or more” means m is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(A) is shownattached.

Thus, in embodiments wherein ring A is a moiety having 4 substitutablehydrogen atoms, m is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring A is a moiety having 4 substitutable hydrogenatoms, m is 0, 1, 2, or 3. In an alternative of such embodiments whereinring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, or2. In an alternative of such embodiments wherein ring A is a moietyhaving 3 substitutable hydrogen atoms, m is 0 or 1. In alternative ofsuch embodiments wherein ring A is a moiety having 3 substitutablehydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 3 substitutablehydrogen atoms, m is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring A is a moiety having 3 substitutable hydrogenatoms, m is 0, 1, or 2. In an alternative of such embodiments whereinring A is a moiety having 3 substitutable hydrogen atoms, m is 0 or 1.In alternative of such embodiments wherein ring A is a moiety having 3substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 2 substitutablehydrogen atoms, m is 0, 1, or 2. In an alternative of such embodimentswherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0or 1. In alternative of such embodiments wherein ring A is a moietyhaving 2 substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 1 substitutablehydrogen atom, m is 0 or 1. In an alternative of such embodimentswherein ring A is a moiety having 1 substitutable hydrogen atoms, m is0.

The following alternatives of R^(L) are applicable to any of theembodiments described hereinabove.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is selected from the group consisting of lower alkyl and lowerheteroalkyl, wherein said lower alkyl and lower heteroalkyl of R^(L) areeach optionally unsubstituted or substituted with one or more halogen.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, propyl, butyl,—CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂CH₂OCH₃, —CH₂SCH₃, —CH₂SCH₂CH₃, —CH₂CH₂SCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂SCH₃, —CH₂N(CH₃)₂,—CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein q, L_(B), ring B, p, and R^(B) are each as defined in Formula(I).

In some embodiments, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0. In such embodiments, -L_(B)- is absent; R^(L) is a moiety havingthe formula

and ring B and -L₁- are directly connected as

shown:

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiazolyl,benzoxazolyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, imidazopyridinyl, indolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl,pyrazolopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, andthienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of furanyl,imidazopyridinyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, phenyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of imidazopyridinyl,isoxazolyl, oxadiazoyl, oxazolyl, phenyl, pyrazolopyridinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyrazolyl, thiadiazolyl and thiazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl,oxadiazoyl, isoxazolyl, oxazolyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazolyl,        oxazolyl, and pyrrolyl is optionally substituted with from 1 to        3 substituents independently selected from the group consisting        of F, Cl, —CN, —CH₃, —OCH₃, and —CF₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH,—C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and—OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—;

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiazolyl,benzoxazolyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF,—CHF, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl,oxadiazoyl, isoxazolyl, oxazolyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazolyl,        oxazolyl, and pyrrolyl is optionally substituted with from 1 to        3 substituents independently selected from the group consisting        of F, Cl, CN, —CH₃, —OCH₃, and —CF₃.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—;

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, imidazopyridinyl, indolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl,pyrazolopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, andthienyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH,—C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and—OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—;

ring B is selected from the group consisting of furanyl,imidazopyridinyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, phenyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, -L_(B)- is—CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0; and R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of imidazopyridinyl,isoxazolyl, oxadiazoyl, oxazolyl, phenyl, pyrazolopyridinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyrazolyl, thiadiazolyl and thiazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

It shall be understood that the phrase “p is 0 or more” means p is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(B) is shownattached.

Thus, in embodiments wherein ring B is a moiety having 4 substitutablehydrogen atoms, p is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring B is a moiety having 4 substitutable hydrogenatoms, p is 0, 1, 2, or 3. In an alternative of such embodiments whereinring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, or2. In an alternative of such embodiments wherein ring B is a moietyhaving 3 substitutable hydrogen atoms, p is 0 or 1. In alternative ofsuch embodiments wherein ring B is a moiety having 3 substitutablehydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 3 substitutablehydrogen atoms, p is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring B is a moiety having 3 substitutable hydrogenatoms, p is 0, 1, or 2. In an alternative of such embodiments whereinring B is a moiety having 3 substitutable hydrogen atoms, p is 0 or 1.In alternative of such embodiments wherein ring B is a moiety having 3substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 2 substitutablehydrogen atoms, p is 0, 1, or 2. In an alternative of such embodimentswherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0or 1. In alternative of such embodiments wherein ring B is a moietyhaving 2 substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 1 substitutablehydrogen atom, p is 0 or 1. In an alternative of such embodimentswherein ring B is a moiety having 1 substitutable hydrogen atoms, p is0.

In an alternative of each of the embodiments described herein, -L₁- isselected from the group consisting of —C(O)NH—, —NHC(O)—, —C(S)NH—,—NHC(S)—, —NH—, —O—CH₂—, —CH₂—O—, —NHCH₂—, and —CH₂NH—.

In another alternative of each of the embodiments described herein, -L₁-is selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(S)NH—,—NHC(S)—, —NH—, —O—CH₂—, and —CH₂—O—.

In another alternative of each of the embodiments described herein, -L₁-is selected from the group consisting of —C(O)NH—, and —NHC(O)—.

In another alternative of each of the embodiments described herein, -L₁-is —C(O)NH—.

As noted above, -L₁- (and -L_(B)- when present) represents a divalentmoiety. The orientation of such divalent moieties in the formula is thesame as the orientation of the moiety as written. Thus, when -L₁- is a—C(O)NH— group, the moiety R^(L)-L₁- has the formula: R^(L)—C(O)NH—. Forexample, when R^(L) is the moiety

and -L₁- is a —C(O)NH— group, the moiety

has the formula:

Specific non-limiting examples of compounds of the invention are shownin the tables of examples below. While only one tautomeric form of eachcompound is shown in the tables, it shall be understood that alltautomeric forms of the compounds are contemplated as being within thescope of the non-limiting examples.

In another embodiment, 1 to 3 carbon atoms of the compounds of theinvention may be replaced with 1 to 3 silicon atoms so long as allvalency requirements are satisfied.

In another embodiment, there is provided a composition comprising acompound of the invention and a pharmaceutically acceptable carrier ordiluent.

Another embodiment provides a composition comprising a compound of theinvention, either as the sole active agent, or optionally in combinationwith one or more additional therapeutic agents, and a pharmaceuticallyacceptable carrier or diluent. Non-limiting examples of additionaltherapeutic agents which may be useful in combination with the compoundsof the invention include those selected from the group consisting of:(a) drugs that may be useful for the treatment of Alzheimer's diseaseand/or drugs that may be useful for treating one or more symptoms ofAlzheimer's disease, (b) drugs that may be useful for inhibiting thesynthesis Aβ, (c) drugs that may be useful for treatingneurodegenerative diseases, and (d) drugs that may be useful for thetreatment of type II diabetes and/or one or more symptoms or associatedpathologies thereof.

Non-limiting examples of additional therapeutic agents which may beuseful in combination with the compounds of the invention include drugsthat may be useful for the treatment, prevention, delay of onset,amelioration of any pathology associated with Aβ and/or a symptomthereof. Non-limiting examples of pathologies associated with Aβinclude: Alzheimer's Disease, Down's syndrome, Parkinson's disease,memory loss, memory loss associated with Alzheimer's disease, memoryloss associated with Parkinson's disease, attention deficit symptoms,attention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and/orDown's syndrome, dementia, stroke,microgliosis and brain inflammation, pre-senile dementia, seniledementia, dementia associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, progressive supranuclear palsy,cortical basal degeneration, neurodegeneration, olfactory impairment,olfactory impairment associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloidangiopathy, hereditary cerebral hemorrhage, mild cognitive impairment(“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysiscomplications (from β₂ microglobulins and complications arisingtherefrom in hemodialysis patients), scrapie, bovine spongiformencephalitis, and Creutzfeld-Jakob disease, comprising administering tosaid patient at least one compound of the invention, or a tautomer orisomer thereof, or pharmaceutically acceptable salt or solvate of saidcompound or said tautomer, in an amount effective to inhibit or treatsaid pathology or pathologies.

Non-limiting examples of additional therapeutic agents for that may beuseful in combination with compounds of the invention include:muscarinic antagonists (e.g., m₁ agonists (such as acetylcholine,oxotremorine, carbachol, or McNa343), or m₂ antagonists (such asatropine, dicycloverine, tolterodine, oxybutynin, ipratropium,methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors(e.g., acetyl- and/or butyrylchlolinesterase inhibitors such asdonepezil (Aricept®,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride), galantamine (Razadyne®), and rivastigimine (Exelon®);N-methyl-D-aspartate receptor antagonists (e.g., Namenda® (memantineHCl, available from Forrest Pharmaceuticals, Inc.); combinations ofcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists;gamma secretase modulators; gamma secretase inhibitors; non-steroidalanti-inflammatory agents; anti-inflammatory agents that can reduceneuroinflammation; anti-amyloid antibodies (such as bapineuzemab,Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1receptor inverse agonists or CB1 receptor antagonists; antibiotics;growth hormone secretagogues; histamine H3 antagonists; AMPA agonists;PDE4 inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors(e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); Tauaggregation inhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488(PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulateinsulin, cholesterol lowering agents such as HMG-CoA reductaseinhibitors (for example, statins such as Atorvastatin, Fluvastatin,Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin) and/or cholesterol absorption inhibitors (such asEzetimibe), or combinations of HMG-CoA reductase inhibitors andcholesterol absorption inhibitors (such as, for example, Vytorin®);fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, andAluminium Clofibrate); combinations of fibrates and cholesterol loweringagents and/or cholesterol absorption inhibitors; nicotinic receptoragonists; niacin; combinations of niacin and cholesterol absorptioninhibitors and/or cholesterol lowering agents (e.g., Simcor®(niacin/simvastatin, available from Abbott Laboratories, Inc.); LXRagonists; LRP mimics; H3 receptor antagonists; histone deacetylaseinhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (EpixPharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptormodulators or antagonists; mGluR5 receptor modulators or antagonists;mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1inhibitors; agents that can induce Abeta efflux such as gelsolin;Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; andantihistamines such as Dimebolin (e.g., Dimebon®, Pfizer).

Another embodiment provides a method of preparing a pharmaceuticalcomposition comprising the step of admixing at least one compound of theinvention or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

Another embodiment provides a method of inhibiting β-secretasecomprising exposing a population of cells expressing β-secretase to atleast one compound of the invention, or a tautomer thereof, in an amounteffective to inhibit β-secretase. In one such embodiment, saidpopulation of cells is in vivo. In another such embodiment, saidpopulation of cells is ex vivo. In another such embodiment, saidpopulation of cells is in vitro.

Additional embodiments in which the compounds of the invention may beuseful include: a method of inhibiting β-secretase in a patient in needthereof. A method of inhibiting the formation of Aβ from APP in apatient in need thereof. A method of inhibiting the formation of Aβplaque and/or Aβ fibrils and/or Aβ oligomers and/or senile plaquesand/or neurofibrillary tangles and/or inhibiting the deposition ofamyloid protein (e.g., amyloid beta protein) in, on or aroundneurological tissue (e.g., the brain), in a patient in need thereof.Each such embodiment comprises administering at least one compound ofthe invention, or a tautomer thereof, or pharmaceutically acceptablesalt of said compound or said tautomer, in a therapeutically effectiveamount to inhibit said pathology or condition in said patient.

Additional embodiments in which the compounds of the invention may beuseful include: a method of treating, preventing, and/or delaying theonset of one or more pathologies associated with Aβ and/or one or moresymptoms of one or more pathologies associated with Aft Non-limitingexamples of pathologies which may be associated with Aβ include:Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss,memory loss associated with Alzheimer's disease, memory loss associatedwith Parkinson's disease, attention deficit symptoms, attention deficitsymptoms associated with Alzheimer's disease (“AD”), Parkinson'sdisease, and/orDown's syndrome, dementia, stroke, microgliosis and braininflammation, pre-senile dementia, senile dementia, dementia associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment, olfactory impairment associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis,type II diabetes, hemodialysis complications (from β₂ microglobulins andcomplications arising therefrom in hemodialysis patients), scrapie,bovine spongiform encephalitis, and Creutzfeld-Jakob disease, saidmethod(s) comprising administering to said patient in need thereof atleast one compound of the invention, or a tautomer thereof, orpharmaceutically acceptable salt of said compound or said tautomer, inan amount effective to inhibit said pathology or pathologies.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Alzheimer's disease, wherein said methodcomprises administering an effective (i.e., therapeutically effective)amount of one or more compounds of the invention (or a tautomer thereof,or pharmaceutically acceptable salt of said compound or said tautomer),optionally in further combination with one or more additionaltherapeutic agents which may be effective to treat Alzheimer's diseaseor a disease or condition associated therewith, to a patient in need oftreatment. In embodiments wherein one or more additional therapeuticagents are administered, such agents may be administered sequentially ortogether. Non-limiting examples of associated diseases or conditions,and non-limiting examples of suitable additional therapeutically activeagents, are as described above.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating mild cognitive impairment (“MCI”), whereinsaid method comprises administering an effective (i.e., therapeuticallyeffective) amount of one or more compounds of the invention (or atautomer thereof, or pharmaceutically acceptable salt of said compoundor said tautomer) to a patient in need of treatment. In one suchembodiment, treatment is commenced prior to the onset of symptoms.

Another embodiment in which the compounds of the invention may be usefulincludes a method of preventing, or alternatively of delaying the onset,of mild cognitive impairment or, in a related embodiment, of preventingor alternatively of delaying the onset of Alzheimer's disease. In suchembodiments, treatment can be initiated prior to the onset of symptoms,in some embodiments significantly before (e.g., from several months toseveral years before) the onset of symptoms to a patient at risk fordeveloping MCI or Alzheimer's disease. Thus, such methods compriseadministering, prior to the onset of symptoms or clinical or biologicalevidence of MCI or Alzheimer's disease (e.g., from several months toseveral yeards before, an effective (i.e., therapeutically effective),and over a period of time and at a frequency of dose sufficient for thetherapeutically effective degree of inhibition of the BACE enzyme overthe period of treatment, an amount of one or more compounds of theinvention (or a tautomer thereof, or pharmaceutically acceptable salt ofsaid compound or said tautomer) to a patient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Down's syndrome, comprising administeringan effective (i.e., therapeutically effective) amount of one or morecompounds of the invention (or a tautomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound or said tautomer) to apatient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a kit comprising, in separate containers, in a single package,pharmaceutical compositions for use in combination, wherein onecontainer comprises an effective amount of a compound of the invention(or a tautomer thereof, or pharmaceutically acceptable salt of saidcompound or said tautomer) in a pharmaceutically acceptable carrier, andanother container (i.e., a second container) comprises an effectiveamount of another pharmaceutically active ingredient, the combinedquantities of the compound of the invention and the otherpharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid proteinin, on or around neurological tissue (e.g., the brain), or (c) treatneurodegenerative diseases, or (d) inhibit the activity of BACE-1 and/orBACE-2.

In various embodiments, the compositions and methods disclosed above andbelow wherein the compound(s) of the invention is a compound orcompounds selected from the group consisting of the exemplary compoundsof the invention described herein.

In another embodiment, the invention provides methods of treating adisease or pathology, wherein said disease or pathology is Alzheimer'sdisease, olfactory impairment associated with Alzheimer's disease,Down's syndrome, olfactory impairment associated with Down's syndrome,Parkinson's disease, olfactory impairment associated with Parkinson'sdisease, stroke, microgliosis brain inflammation, pre-senile dementia,senile dementia, progressive supranuclear palsy, cortical basaldegeneration, β-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma,amyloidosis, type II diabetes, diabetes-associated amyloidogenesis,scrapie, bovine spongiform encephalitis, traumatic brain injury, orCreutzfeld-Jakob disease, said method comprising administering acompound of the invention, or a pharmaceutically acceptable salt of saidcompound or said tautomer, to a patient in need thereof in an amounteffective to treat said disease or pathology.

In another embodiment, the invention provides for the use of any of thecompounds of the invention for use as a medicament, or in medicine, orin therapy.

In another embodiment, the invention provides for use of a compound ofthe invention for the manufacture of a medicament for the treatment of adisease or pathology, wherein said disease or pathology is Alzheimer'sdisease, olfactory impairment associated with Alzheimer's disease,Down's syndrome, olfactory impairment associated with Down's syndrome,Parkinson's disease, olfactory impairment associated with Parkinson'sdisease, stroke, microgliosis brain inflammation, pre-senile dementia,senile dementia, progressive supranuclear palsy, cortical basaldegeneration, β-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma,amyloidosis, type II diabetes, diabetes-associated amyloidogenesis,scrapie, bovine spongiform encephalitis, traumatic brain injury, orCreutzfeld-Jakob disease.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of “alkyl” applies to“alkyl” as well as the “alkyl” protion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not explicitly defined in the context ofthe embodiment is as defined in Formula (I). All valences not explicitlyfilled are assumed to be filled by hydrogen.

“Patient” includes both human and non-human animals. Non-human animalsinclude those research animals and companion animals such as mice,primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g.,house cats).

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

“Halogen” (or “halo”) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight orbranched, comprising 1 to about 10 carbon atoms. “Lower alkyl” means astraight or branched alkyl group comprising 1 to about 4 carbon atoms.Branched means that one or more lower alkyl groups such as methyl, ethylor propyl, are attached to a linear alkyl chain. Non-limiting examplesof suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, i-butyl, and t-butyl.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroalkyl” means an alkyl moiety as defined above, which issubstituted by one or more (e.g., one, two, or three) moietiesindependently selected from the group consisting of: —O-alkyl, —S-alkyl,—S(O)-alkyl, —S(O)₂-alkyl, —N(H)alkyl, and —N(alkyl)₂.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 10 carbon atoms in the straight or branchedchain. Branched means that one or more lower alkyl groups such asmethyl, ethyl propyl, ethenyl or propenyl are attached to a linear orbranched alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 10 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, orlower alkenyl or lower alkynyl groups, are attached to a linear alkynylchain. “Lower alkynyl” means about 2 to about 4 carbon atoms in thechain which may be straight or branched. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl and3-methylbutynyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl. “Monocyclic aryl” means phenyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or moresubstituents, which may be the same or different, as defined herein. Theprefix aza, oxa or thia before the heteroaryl root name means that atleast a nitrogen, oxygen or sulfur atom respectively, is present as aring atom. A nitrogen atom of a heteroaryl can be optionally oxidized tothe corresponding N-oxide. “Heteroaryl” may also include a heteroaryl asdefined above fused to an aryl as defined above. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl(which alternatively may be referred to as thiophenyl), pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term“monocyclic heteroaryl” refers to monocyclic versions of heteroaryl asdescribed above and includes 4- to 7-membered monocyclic heteroarylgroups comprising from 1 to 4 ring heteroatoms, said ring heteroatomsbeing independently selected from the group consisting of N, O, and S,and oxides thereof. The point of attachment to the parent moiety is toany available ring carbon or ring heteroatom. Non-limiting examples ofmonocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl),imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof

“Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 3 to about6 carbon atoms. The cycloalkyl can be optionally substituted with one ormore substituents, which may be the same or different, as describedherein. Monocyclic cycloalkyl refers to monocyclic versions of thecycloalkyl moieties described herein. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of multicycliccycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl,adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contain at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or moresubstituents, which may be the same or different, as described herein.The term “monocyclic cycloalkenyl” refers to monocyclic versions ofcycloalkenyl groups described herein and includes non-aromatic 3- to7-membered monocyclic cycloalkyl groups which contains one or morecarbon-carbon double bonds. Non-limiting examples include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl,cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitablemulticyclic cycloalkenyl is norbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appearsin a definition of a variable in a general structure described herein,refers to the corresponding N-oxide, S-oxide, or S,S-dioxide.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):

As used herein, the term “monocyclic heterocycloalkyl” refers monocyclicversions of the heterocycloalkyl moities described herein and include a4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to4 ring heteroatoms, said ring heteroatoms being independently selectedfrom the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂.The point of attachment to the parent moiety is to any available ringcarbon or ring heteroatom. Non-limiting examples of monocyclicheterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam,delta lactam, beta lactone, gamma lactone, delta lactone, andpyrrolidinone, and oxides thereof. Non-limiting examples of loweralkyl-substituted oxetanyl include the moiety:

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitableheterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidinone (orpyrrolone):

As used herein, the term “monocyclic heterocycloalkenyl” refers tomonocyclic versions of the heterocycloalkenyl moities described hereinand include 4- to 7-membered monocyclic heterocycloalkenyl groupscomprising from 1 to 4 ring heteroatoms, said ring heteroatoms beingindependently selected from the group consisting of N, N-oxide, O, S,S-oxide, S(O), and S(O)₂. The point of attachment to the parent moietyis to any available ring carbon or ring heteroatom. Non-limitingexamples of monocyclic heterocyloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, andoxides thereof

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom.

there is no —OH attached directly to carbons marked 2 and 5.

“Arylalkyl” (or “aralkyl”) means an aryl-alkyl- group in which the aryland alkyl are as previously described, except that in this context the“alkyl” portion of the “arylalkyl” (or “-alkyl-aryl”) group refers to astraight or branched lower alkyl group. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl. The term (and similar terms) may bewritten as “arylalkyl-” (or as “-alkyl-aryl”) to indicate the point ofattachment to the parent moiety. Similarly, “heteroarylalkyl”,“cycloalkylalkyl”, “cycloalkenylalkyl”, “heterocycloalkylalkyl”,“heterocycloalkenylalkyl”, etc., mean a heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as describedherein bound to a parent moiety through an alkyl group. As indicatedabove, the “alkyl” group in this context represents a lower alkyl group,which may be straight or branched, or unsubstituted and/or substitutedas described herein.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

Any of the foregoing functional groups may be unsubstituted orsubstituted as described herein. The term “substituted” means that oneor more hydrogens on the designated atom is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency under the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. By “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The term “optionally substituted” meansoptional substitution with the specified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl-moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁶ in —N(R⁶)₂,or a variable appears more than once in a structure presented herein,the variables can be the same or different.

The line

, as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example:

means containing both

The wavy line

, as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

In another embodiment, the compounds of the invention, and/orcompositions comprising them, are present in isolated and/or purifiedform. The term “purified”, “in purified form” or “in isolated andpurified form” for a compound refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound (or atautomer thereof, or pharmaceutically acceptable salt of said compoundor said tautomer) after being obtained from a purification process orprocesses described herein or well known to the skilled artisan (e.g.,chromatography, recrystallization and the like), in sufficient purity tobe suitable for in vivo or medicinal use and/or characterizable bystandard analytical techniques described herein or well known to theskilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

Those skilled in the art will recognize those instances in which thecompounds of the invention may be converted to prodrugs and/or solvates,another embodiment of the present invention. A discussion of prodrugs isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems (1987) 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, (1987) Edward B. Roche, ed., AmericanPharmaceutical Association and Pergamon Press. The term “prodrug” meansa compound (e.g, a drug precursor) that is transformed in vivo to yielda compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (e.g., by metabolic or chemical processes), such as,for example, through hydrolysis in blood. A discussion of the use ofprodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms where they exist. “Solvate”means a physical association of a compound of the invention with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. Thus, reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes any of thefollowing: acidic salts formed with inorganic and/or organic acids, aswell as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also potentially useful. Salts of the compounds of the invention maybe formed by methods known to those of ordinary skill in the art, forexample, by reacting a compound of the invention with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts which may be useful include acetates,ascorbates, benzoates, benzenesulfonates, bisulfates, borates,butyrates, citrates, camphorates, camphorsulfonates, fumarates,hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,methanesulfonates, naphthalenesulfonates, nitrates, oxalates,phosphates, propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered as potentially useful alternatives to the freeforms of the corresponding compounds for purposes of the invention.

Another embodiment which may be useful includes pharmaceuticallyacceptable esters of the compounds of the invention. Such esters mayinclude the following groups: (1) carboxylic acid esters obtained byesterification of the hydroxy groups, in which the non-carbonyl moietyof the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

As mentioned herein, under certain conditions the compounds of theinvention may form tautomers. Such tautomers, when present, compriseanother embodiment of the invention. It shall be understood that alltautomeric forms of such compounds are within the scope of the compoundsof the invention. For example, all keto-enol and imine-enamine forms ofthe compounds, when present, are included in the invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Where various stereoisomers of the compounds of the invention arepossible, another embodiment provides for diastereomeric mixtures andindividual enantiomers of the compounds of the invention. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by reaction withan appropriate optically active compound (e.g., chiral auxiliary such asa chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Also, some of thecompounds of the invention may be atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention. Enantiomers canalso be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds of the invention (including those of thesalts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated as embodiments within the scope of this invention, as arepositional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (Forexample, if a compound of the invention incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Another embodiment which may be useful include isotopically-labelledcompounds of the invention. Such compounds are identical to thoserecited herein, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁴N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Another embodiment provides suitable dosages and dosage forms of thecompounds of the invention. Suitable doses for administering compoundsof the invention to patients may readily be determined by those skilledin the art, e.g., by an attending physician, pharmacist, or otherskilled worker, and may vary according to patient health, age, weight,frequency of administration, use with other active ingredients, and/orindication for which the compounds are administered. Doses may rangefrom about 0.001 to 500 mg/kg of body weight/day of the compound of theinvention. In one embodiment, the dosage is from about 0.01 to about 25mg/kg of body weight/day of a compound of the invention, or apharmaceutically acceptable salt or solvate of said compound. In anotherembodiment, the quantity of active compound in a unit dose ofpreparation may be varied or adjusted from about 1 mg to about 100 mg,preferably from about 1 mg to about 50 mg, more preferably from about 1mg to about 25 mg, according to the particular application. In anotherembodiment, a typical recommended daily dosage regimen for oraladministration can range from about 1 mg/day to about 500 mg/day,preferably 1 mg/day to 200 mg/day, in two to four divided doses.

When used in combination with one or more additional therapeutic agents,the compounds of this invention may be administered together orsequentially. When administered sequentially, compounds of the inventionmay be administered before or after the one or more additionaltherapeutic agents, as determined by those skilled in the art or patientpreference.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, another embodiment provides combinations comprising anamount of at least one compound of the invention, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof, and an effectiveamount of one or more additional agents described above.

Another embodiment provides for pharmaceutically acceptable compositionscomprising a compound of the invention, either as the neat chemical oroptionally further comprising additional ingredients. For preparingpharmaceutical compositions from the compounds of the invention, inert,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets and suppositories. The powders and tablets may becomprised of from about 5 to about 95 percent active ingredient.Suitable solid carriers are known in the art, e.g., magnesium carbonate,magnesium stearate, talc, sugar or lactose. Tablets, powders, cachetsand capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^(th) Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.Non-limiting examples which may be useful include water orwater-propylene glycol solutions for parenteral injection or addition ofsweeteners and opacifiers for oral solutions, suspensions and emulsions.Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

Another embodiment which may be useful includes compositions comprisinga compound of the invention formulated for transdermal delivery. Thetransdermal compositions can take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

Other embodiment which may be useful includes compositions comprising acompound of the invention formulated for subcutaneous delivery or fororal delivery. In some embodiments, it may be advantageous for thepharmaceutical preparation comprising one or more compounds of theinvention be prepared in a unit dosage form. In such forms, thepreparation may be subdivided into suitably sized unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose. Each of the foregoingalternatives, together with their corresponding methods of use, areconsidered as included in the various embodiments of the invention.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in theart. The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable. Reactions may involve monitoring for consumption of startingmaterial, and there are many methods for said monitoring, including butnot limited to thin layer chromatography (TLC) and liquid chromatographymass spectrometry (LCMS), and those skilled in the art will recognizethat where one method is specified, other non-limiting methods may besubstituted.

Techniques, solvents and reagents may be referred to by theirabbreviations as follows:

-   -   Acetic acid: AcOH Inhibition: Inh.    -   Acetonitrile: MeCN Iron(III) acetylacetonate: Fe(acac)₃    -   Aqueous: aq. 35 Liquid chromatography mass    -   Benzyl: Bn Spectrometry: LCMS    -   tert-Butyl: t-Bu or tBu Methanesulfonyl chloride: MsCl    -   Centimeters: cm Methanol: MeOH    -   Dichloromethane: DCM Methyl iodide: MeI    -   Diisopropylamine: iPr₂NH or DIPA Microliters: μl or μL    -   Diisopropylethylamine: DIEA or iPr₂NEt Milligrams: mg    -   Dimethylformamide: DMF Milliliters: mL    -   Dimethylsulfoxide: DMSO Millimoles: mmol    -   Ether or diethyl ether: Et₂O Minutes: min    -   Ethanol: EtOH n-Butyllithium: nBuLi or n-BuLi    -   Ethyl: Et Nuclear magnetic resonance spectroscopy: NMR    -   Ethyl acetate: AcOEt, EtOAc, or EA    -   Example: Ex. Para-methoxy benzyl: PMB    -   Grams: g Petroleum ether: PE    -   Hexanes: hex Retention time: t_(R) or Ret. Time    -   High performance liquid chromatography: Room temperature        (ambient, about 25° C.):    -   HPLC rt or RT    -   tert-Butoxycarbonyl: t-Boc or Boc Triethylamine: Et₃N or TEA    -   Temperature: temp. Trifluoroacetic acid: TFA    -   Tetrahydrofuran: THF    -   2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4-6-trioxide:        T3P        Method A:

Step 1:

To a stirred solution of compound A1 (200 g, 1.46 mol) in pyridine (400mL) was added MsCl (167 g, 1.46 mol) dropwise via an addition funnel at0° C. After the addition was completed, the mixture was stirred at roomtemperature for 6 h. After that time, the reaction was concentratedunder vacuum. To the residue was added CH₂Cl₂ (1 L) and the resultingmixture was washed with 1N HCl_((aq.))(2×1 L), sat. NaHCO_(3(aq.)) (2×1L) and brine (500 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated to afford crude product, which waswashed with (petroleum ether/ethyl acetate, 2:1, 300 mL). The productwas isolated by filtration and the solid was dried under vacuum. To asolution of the solid (220 g, 1.02 mol) in DMF (1100 mL) at 0° C. wasadded Cs₂CO₃ (500 g, 1.53 mol) followed by the dropwise addition of CH₃I(188.6 g, 1.33 mol). The mixture was stirred at room temperatureovernight. The reaction was then poured into cold water which caused asolid to precipitate. The solid was removed via filtration and washedwith water. The solid was then dissolved in CH₂Cl₂ (3 L), and theresulting solution was washed with brine (500 mL), dried over anhydrousNa₂SO₄, filtered and dried under vacuum to afford compound A2.

Step 2:

To a solution of 90% HNO₃ (2 mL) at −40° C. was added compound A3 (500mg, 3.4 mmol) dropwise over 15 min. The resulting solution was stirredat −40° C. for 30 min. The reaction was then slowly poured into icewater and the resultant mixture was extracted with dichloromethane (50mL). The combined organic layers were washed successively with sat.NaHCO₃ (aq.), water and brine. The organic layer was then dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford A4.¹H NMR (DMSO-d₆, 300 MHz): 8.46 (d, J=2.91 Hz, 1H), 8.37 (dd, J=2.91 Hz,J=9.15 Hz, 1H), 7.27 (d, J=9.15 Hz, 1H), 4.70 (d, J=6.36 Hz, 2H), 2.90(d, J=6.39 Hz, 2H). MS: ES/APCI-MS [M−H⁺] m/z 192.2.

Step 3:

To a stirred solution of compound A4 (1.0 g, 5.5 mmol) intetrahydrofuran (10 mL) under nitrogen was added (R)-(+)-t-butylsulfinamide (727 mg, 6.0 mmol) followed by Ti(OEt)₄ (1.6 mL, 6.8 mmol).The reaction mixture was heated to reflux for 18 h. After that time, thereaction mixture was cooled to RT and diluted with ice water. Themixture was filtered through a pad of celite. The filter pad wasthoroughly washed with dichloromethane. The phases of the filtrate wereseparated. The organic layer was washed with water and brine then driedover anhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by column chromatography over silica gel (gradient 12-15% ethylacetate in petroleum ether) to obtain compound A5. ¹H NMR (DMSO-d₆, 400MHz): 8.65 (d, J=2.88 Hz, 1H), 8.28 (dd, J=2.88 Hz, J=9.12 Hz, 1H), 7.22(d, J=9.16 Hz, 1H), 4.53-4.48 (m, 2H), 3.41-3.37 (m, 2H), 1.24 (s, 9H).

Step 4:

To a solution of compound A2 (905 mg, 3.06 mmol) in tetrahydrofuran (15mL) at −78° C. was added n-BuLi (1.8 mL, 4.4 mmol, 2.5 M in hexane)dropwise. The reaction mixture was stirred for 30 min at −78° C. To themixture was then added a solution of compound A5 (1 g, 4.4 mmol) intetrahydrofuran (15 mL) and the mixture was stirred for 3.5 h at −78° C.The reaction mixture was quenched with saturated NH₄Cl_((aq.)) (20 mL)and the resulting mixture was warmed to RT. The mixture was thenextracted with ethyl acetate. The combined organic layers were washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The crude residue was purified by flash column chromatographyover silica gel (gradient 15-20% ethyl acetate in petroleum ether) toyield compound A6. ¹H NMR (DMSO-d₆, 300 MHz): 8.17 (d, J=2.67 Hz, 1H),8.10-8.06 (m, 1H), 7.28-7.25 (m, 2H), 6.99-6.89 (m, 3H), 4.65-4.57 (m,1H), 4.42-4.35 (m, 2H), 4.27-4.24 (m, 1H), 4.15-4.07 (m, 1H), 3.81 (s,3H), 3.32-3.20 (m, 2H), 2.90-2.84 (m, 1H), 2.82 (s, 3H), 1.29 (s, 9H).MS: ES/APCI-MS [M+H⁺] m/z 526.2.

Step 5:

To a solution of the sulfinamide A6 (1.0 g, 1.90 mmol) indichloromethane (10 mL) was added a solution of HCl (4 M in dioxane, 3mL). The resultant solution was stirred at room temperature for 1 h.After that time, the solution was concentrated in vacuo. The obtainedresidue was dissolved in trifluoroacetic acid (10 mL). To this mixturewas added thioglycolic acid (1.73 mL, 23.8 mmol). The resultant mixturewas stirred at room temperature overnight and concentrated. The residuewas partitioned between DCM and NaHCO_(3 (aq.)) and the layers wereseparated. The organic layer was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated. The crude residue was purified byflash column chromatography over silica gel (gradient elution: 55-60%ethyl acetate in petroleum ether) to afford compound A7. ¹H NMR(DMSO-d₆, 300 MHz): 8.51 (d, J=2.79 Hz, 1H), 8.01 (dd, J=2.82 Hz, J=9.06Hz, 1H), 6.93 (d, J=9.06 Hz, 1H), 4.40-4.36 (m, 2H), 4.08-4.06 (m, 1H),3.63 (d, J=14.46 Hz, 1H), 3.48 (d, J=14.46 Hz, 1H), 3.15 (d, J=5.19 Hz,1H), 2.58 (s, 3H). MS: ES/APCI-MS [M+H⁺] m/z 302.0.

Step 6:

To a slurry of the amine A7 (340 mg 1.13 mmol) in n-butanol (5 mL) andacetonitrile (5 mL) was added cyanogen bromide (593 mg, 5.65 mmol). Theresultant mixture was heated to reflux and stirred for 16 h. The mixturewas then concentrated and purified by flash column chromatography oversilica gel (gradient elution 80-90% ethyl acetate in petroleum ether) toafford compound A8.

Step 7:

To a solution of compound A8 (180 mg, 0.553 mmol) in dichloromethane wasadded Boc₂O (0.18 mL, 0.828 mmol) and triethylamine (0.19 mL, 1.38mmol). The resultant mixture was stirred at room temperature overnight.The mixture was then diluted with water and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, and concentrated. The crude product waspurified by flash column chromatography over silica gel (gradientelution 15-25% ethyl acetate in petroleum ether) to afford compound A9.¹H NMR (CD₃OD, 400 MHz): 8.45 (d, J=2.40 Hz, 1H), 8.16 (dd, J=2.48 Hz,J=9.08 Hz, 1H), 7.03 (d, J=9.12 Hz, 1H), 4.54-4.50 (m, 1H), 4.48-4.40(m, 1H), 4.39-4.32 (m, 1H), 4.27-4.23 (m, 1H), 3.29 (s, 3H), 2.91-2.87(m, 1H), 2.53-2.49 (m, 1H), 1.29 (s, 9H). MS: 98.46%; ES/APCI-MS [M+H⁺]m/z 427.

Step 8.

A solution of compound A9 (120 mg, 0.281 mmol) in methanol (2 mL) wasdegassed with nitrogen for 5 min. To the solution was added Pd/C (20%w/w, 50% H₂O, 25 mg). The resulting mixture was stirred at roomtemperature under a hydrogen balloon for 2 h. After that time, thereaction mixture was filtered through celite and concentrated. The cruderesidue was purified by flash column chromatography over silica gel(gradient elution 55-60% ethyl acetate in petroleum ether) to affordcompound A10. ¹H NMR (CD₃OD, 400 MHz): 6.81 (d, J=2.52 Hz, 1H),6.71-6.66 (m, 2H), 4.29-4.23 (m, 2H), 4.15-4.10 (m, 2H), 3.17 (s, 3H),2.80-2.74 (m, 1H), 2.44-2.41 (m, 1H), 1.44 (s, 9H). MS: ES/APCI-MS[M+H⁺] m/z 397.2.

Step 9:

To a solution of 5-chloropicolinic acid (71 mg, 0.621 mmol) intetrahydrofuran (2 mL) at room temperature under nitrogen was addedN,N-diisopropylethylamine (0.21 mL, 1.134 mmol) and 50% solution of T₃Pin ethyl acetate (0.17 mL, 0.529 mmol). The reaction mixture was stirredat room temperature for 15 min. After that time, aniline A10 (150 mg,0.378 mmol) dissolved in THF (3 mL) was added slowly and the reactionmixture was stirred at room temperature for 3 h. Water was added to thereaction and the mixture was extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over anhydrousNa₂SO₄ and concentrated. The crude residue was purified by flash columnchromatography over silica gel (gradient elution 22-25% ethyl acetate inpetroleum ether) to afford A11. MS: ES/APCI-MS [M⁺] m/z 536.0.

Step 10:

To a solution of compound A11 (120 mg, 0.223 mmol) in DCM (2 mL) at 0°C. was added HCl (4M in dioxane, 2 mL). The reaction was warmed to RTand stirred for 2 h at which point the reaction mixture was concentratedin vacuo. The crude residue was purified by flash column chromatographyover silica gel (10-15% methanol in dichloromethane) to afford Example1a.

¹H NMR (DMSO-d₆, 400 MHz): 10.48 (s, 1H), 10.23 (bs, 1H), 8.78 (s, 1H),8.45 (bs, 1H), 8.35-8.33 (m, 1H), 8.22-8.20 (m, 1H), 7.97 (d, J=2.32 Hz,1H), 7.86 (dd, J=2.41 Hz, J=8.92 Hz, 1H), 6.90 (d, J=8.92 Hz, 1H),4.86-4.82 (m, 1H), 4.39-4.31 (m, 1H), 4.27-4.19 (m, 2H), 3.35 (s, 3H),2.63-2.60 (m, 1H), 2.49-2.46 (m, 1H). MS: ES/APCI-MS [M+H⁺] m/z 436.0.

The examples in Table 1 were prepared using procedures similar to thosedescribed in Method A using the requisite carboxylic acid in step 9.

TABLE 1 LCMS data Ex. t_(R) BACE1 BACE2 no. Example m/z (min) ConditionsK_(i) (nM) K_(i) (nM) 1a

436 2.30 1  70  17 1b

432 2.21 1  233 130 1c

369 1.81 1 2008 341 1d

375 1.87 1 2275 728Method B:

Parallel preparation of Examples 2a-2w: To a set of vials containing therequisite carboxylic acid (0.076 mmol) was added a solution of A10 (25mg, 0.063 mmol) in DCM (0.75 mL) followed by the addition of iPr₂NEt(0.033 mL, 0.19 mmol) and a solution of T3P (50% in EtOAc, 0.075 mL,0.13 mmol). The vials were capped and the mixtures were shaken at RTovernight. After that time, water (0.050 mL) and TFA (0.50 mL) wereadded to each vial. The mixtures were then shaken at RT for 3 hours.After that time, the mixtures were concentrated in vacuo. The cruderesidues were dissolved in DMSO (1 mL) and filtered. The crude productswere purified by mass triggered HPLC using the following conditions:[column: Waters Sunfire C18, 5 μm, 19×100 mm; solvent: gradient range10% initial to 18-29% final MeCN (0.1% formic acid) in water (0.1%formic acid) 25 mL/min; 9-12 min run time] to afford Examples 2a-2w.

TABLE 2 LCMS data Ex. t_(R) BACE1 BACE2 no. Example m/z (min) ConditionsK_(i) (nM) K_(i) (nM) 2a

450.12 0.82 2  91  59 2b

406.11 0.67 2 142  20 2c

427.11 0.76 2  26  51 2d

471.1  0.76 2 579 780 2e

454.07 0.82 2  49  9 2f

457.12 0.85 2  13 138 2g

501.11 0.96 2  70 699 2h

456.13 0.87 2  33 313 2i

446.14 0.87 2 168  29 2j

447.14 0.87 2 294 160 2k

441.13 0.80 2  15  26 2l

433.12 0.78 2 212 254 2m

471.1  0.88 2 303 1150  2n

441.13 0.79 2 1488  337 2o

470.1  0.94 2  77 283 2p

441.11 0.74 2  20  3 2q

407.11 0.63 2 367  31 2r

466.12 0.74 2 604 6912  2s

409.07 0.68 2 240  46 2t

420.11 0.79 2 205  31 2u

468.11 0.88 2  44 166 2v

486.1  0.97 2  52 261 2w

465.13 0.81 2 229 572Method C:

Step 1:

NaH (1.8 g, 46.6 mmol) was added to a THF (60 mL) solution of2-iodo-benzyl alcohol C1 (7.3 g, 31.19 mmol) at 0° C., in smallportions. After the complete addition of NaH, allyl bromide (3.9 mL,46.73 mmol) was added. The mixture was stirred overnight at roomtemperature. The resultant heterogeneous mixture was quenched with asaturated cold NH₄Cl_((aq.)) solution and extracted with ethyl acetate.The combined organic layers were washed with H₂O and brine, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The crude residue waspurified by flash chromatography over silica gel using 5% ethyl acetatein petroleum ether as the eluent to yield C2. ¹H-NMR (CDCl₃, 400 MHz): δ7.83 (dd, J=7.6, 0.8 Hz, 1H), 7.47 (d, J=6.4 Hz, 1H), 7.36 (dt, J=7.6,0.8 Hz, 1H), 6.99 (dt, J=7.6, 1.6 Hz, 1H), 6.05-5.96 (m, 1H), 5.40-5.39(m, 0.5H), 5.35-5.34 (m, 0.5H), 5.25 (dd, J=10.4, 1.6 Hz, 1H), 4.51 (s,2H), 4.14-4.12 (m, 2H).

Step 2:

Allyl ether C2 (1.0 g, 3.65 mmol) was dissolved in a mixture of 15 ml ofMeCN and 2.5 mL (18.2 mmol) of Et₃N. The mixture was vacuum degassed (3cycles) followed by the addition of Pd(OAc)₂ (40.88 mg, 0.182 mmol) andPPh₃ (95.73 mg, 0.365 mmol). The mixture was heated to 80° C. for 2 h.The mixture was then cooled to room temperature and diluted with water.The mixture was extracted with ethyl acetate. The organic layer waswashed sequentially with 1N HCl_((aq.)), sat. NaHCO_(3(aq.)) and brine.The organic layer was then dried over Na₂SO₄, filtered and concentratedin vacuo. The crude residue was purified by flash chromatography oversilica gel using a gradient elution of 0-2% ethyl acetate in petroleumether to provide C3. ¹H-NMR (CDCl₃, 400 MHz): δ 7.72-7.69 (m, 1H),7.28-7.24 (m, 2H), 7.07-7.04 (m, 1H), 5.63 (s, 1H), 5.04 (s, 1H), 4.84(s, 2H), 4.47 (s, 2H).

Step 3:

To a mixture of C3 (3.0 g, 20.55 mmol) in dioxane-water (1:1, 40 mL) at0° C. was added NaIO₄ (13.1 g, 61.5 mmol). The reaction mixture wasstirred for 10 min. After that time, a solution of OsO₄ (2.5% int-butanol, 0.104 g, 0.41 mmol) was added dropwise. The reaction wasallowed to warm to RT and stirred overnight. After that time, water wasadded to the reaction flask and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, then driedover Na₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by flash chromatography over silica gel eluting with 10% ethylacetate in petroleum ether to afford C4. ¹H-NMR (CDCl₃, 400 MHz): δ 8.06(d, J=7.7 Hz, 1H), 7.61-7.56 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.24 (d,J=7.6 Hz, 1H), 4.91 (s, 2H), 4.39 (s, 2H).

Step 4:

To a cooled solution of 90% HNO₃ (47.6 mL) at −30° C., C4 (7 g, 47.3mmol) was added dropwise over 30 min. The resultant solution was stirredat −30° C. for 5 h and then slowly poured onto ice. The reaction mixturewas diluted by adding cold water and the mixture was extracted withdichloromethane. The combined organic layers were washed sequentiallywith sat. NaHCO_(3(aq.)), water and brine. The organic layer was thendried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue was purified by flash chromatography over silica gel usinga gradient elution of 30-50% ethyl acetate in petroleum ether to affordC5. ¹H NMR (CDCl₃, 400 MHz): δ. 8.88 (d, J=2.4 Hz, 1H), 8.43 (dd, J=8.4,2.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.00 (s, 2H), 4.45 (s, 2H).

Step 5:

To a solution of C5 (6 g, 31.09 mmol) in THF (80 mL) was added(R)-(+)-2-methyl-2-propanesulfinamide (6.77 g, 55.95 mmol) and Ti(OEt)₄,(12.76 g, 55.96 mmol). The resultant solution was heated to reflux for 1h. After that time, the solution was cooled to RT and poured into icecold water. The mixture was filtered and the filter cake was washed withCH₂Cl₂. The layers were separated and the aqueous layer was extractedwith CH₂Cl₂. The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by flashchromatography over silica gel eluting with 15% ethyl acetate inpetroleum ether to afford C6. ¹H NMR (CDCl₃, 400 MHz): δ. 8.88 (d, J=2Hz, 1H), 8.30 (dd, J=8.2, 2.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 5.24 (d,J=17.2 Hz, 1H), 5.05 (d, J=17.2 Hz, 1H), 4.87 (d, J=2.4 Hz, 2H), 1.38(s, 9H).

Step 6:

To a solution of the sulfonamide A2 (4.64 g, 20.26 mmol) in anhydrousTHF (25 mL) at −78° C. under an atmosphere of N₂ was added dropwise asolution of n-BuLi (2.5 M in hexane, 8.11 mL, 20.28 mmol). The resultantsolution was stirred at −78° C. for 1 h. After that time, a solution ofthe ketimine C6 (3 g, 10.14 mmol) in THF (25 mL) precooled to −78° C. ina separate round bottom flask was transferred via cannula to thesolution above. The resultant solution was stirred at −78° C. for 3.5 h.The reaction was the quenched with a saturated aqueous solution of NH₄Cland the mixture was extracted with EtOAc (3×). The combined organiclayers were washed with water and brine then dried over Na₂SO₄ andconcentrated. The crude residue was purified by flash chromatographyover silica gel eluting with a gradient of 50-60% EtOAc in petroleumether to afford C7.

Step 7:

To a solution of C7 (3.0 g, 5.7 mmol) in dichloromethane (30 mL) wasadded a solution of HCl in dioxane (30 mL, 4.5 M) at 0° C. and theresultant solution was stirred at RT for 3 h. After that time, thereaction mixture was concentrated. To the residue was added TFA (30 mL)at 0° C. followed by the addition of thioglycolic acid (4.14 mL, 57.13mmol). The reaction mixture was stirred RT for 16 h. The solution wasthen concentrated. The residue was partitioned between aq. NaHCO₃ (pH 8)and DCM. The layers were separated and the aqueous layer was extractedwith DCM. The combined extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude residue was purified oversilica gel eluting with 80% EtOAc in petroleum ether to afford C8

Step 8:

To slurry of C8 (1.3 g, 3.98 mmol) in 1:1 mixture of acetonitrile andn-butanol (25 mL:25 mL) was added cyanogen bromide (2.11 g, 19.9 mmol).The resultant mixture was heated to reflux overnight. The reactionmixture was cooled to RT and the volatiles removed under reducedpressure. The crude residue was washed with diethyl ether (3×) and theproduct C9 was isolated via filtration.

Step 9:

To a solution of C9 (1.3 g, 3.99 mmol) in CH₂Cl₂ (25 mL) was added Boc₂O(2.6 mL, 11.93 mmol) and DIEA (3.0 mL, 19.88 mmol). The resultantsolution was stirred at RT overnight. The volatiles were removed underreduced pressure and the crude residue was purified by flashchromatography over silica gel eluting with 20% EtOAc in petroleum etherto afford C10. ¹H NMR (CDCl₃, 400 MHz): δ. 10.56 (s, 1H), 8.36 (d, J=2.0Hz, 1H), 8.21 (dd, J=2.0 & 8.4 Hz, 1H), 7.28 (s, 1H), 5.01-4.86 (m, 2H),4.20 (d, J=14 Hz, 2H), 3.67 (dd, J=1.6 & 11.6 Hz, 1H), 3.51 (dd, J=1.6 &14 Hz, 1H), 3.40 (s, 3H), 1.48 (s, 9H). m/z: 425.02 (M−H; negativemode)⁻

Step 10:

A solution of the C10 (1.3 g, 3.05 mmol) in 1:1 mixture of methanol andethanol (40 mL) was degassed by bubbling N₂ through the solution for 3min. To this solution was added Pd/C (10% w/w, 400 mg). The mixture wasplaced under an atmosphere of N₂. The atmosphere was evacuated andback-filled with hydrogen. The resulting mixture was stirred at RT underan atmosphere of hydrogen for 2 h. The mixture was then filtered throughcelite and concentrated. The crude residue was purified by flashchromatography over silica gel eluting with a gradient 20-30% EtOAc inpetroleum ether to afford C11. ¹H NMR (DMSO-d₆, 400 MHz): δ. 9.95 (s,1H), 6.79-6.76 (m, 1H), 6.71 (s, 1H), 6.57-6.54 (m, 1H), 5.13 (s, 2H),4.64-4.54 (m, 1H), 4.42-4.37 (m, 1H), 4.27-4.23 (m, 1H), 4.04-3.85 (m,3H), 3.12 (s, 3H), 1.36 (s, 9H). m/z: 397.4 (M+H)⁺

Table 3 The following examples were prepared from C11 using therequisite carboxylic acid following procedures similar to thosedescribed in Method A, steps 9-10.

LCMS data Ex. t_(R) BACE1 BACE2 no. Example m/z (min) Conditions K_(i)(nM) K_(i) (nM) 3a

436.3 2.30 1  272  58 3b

432.2 2.24 1 1160 354Method D:

D1 was converted to D2 using conditions similar to those described inMethod B steps 5-11.

Table 4 The following examples were prepared from D2 using the requisitecarboxylic acid following procedures similar to those described inMethod A, steps 9-10.

LCMS data Ex. t_(R) BACE1 BACE2 no. Example m/z (min) Conditions K_(i)(nM) K_(i) (nM) 4a

434.2 2.40 1  58  15 4b

430.2 2.35 1  228  67 4c

367.2 1.99 1 2115 260 4d

373.2 2.07 1 2576 515Method E:

Parallel preparation of Examples 5a-5w: These examples were preparedfrom D2 and the requisite carboxylic acid using a procedure similar tothat described in Method B. The crude products were purified by masstriggered HPLC using the following conditions: [column: Waters XBridgeC18, 5 μm, 19×100 mm; solvent: gradient range 15-30% initial to 50-65%final MeCN (0.1% NH₄OH) in water (0.1% NH₄OH) 50 mL/min; 8 min run time]to afford Examples 5a-5w.

TABLE 5 LCMS data Ex. t_(R) BACE1 BACE2 no. Example m/z (min) ConditionsK_(i) (nM) K_(i) (nM) 5a

464.14 0.81 2 636 1131  5b

418.13 0.86 2 192  28 5c

466.13 0.95 2  59 126 5d

484.12 1.03 2  55 219 5e

463.15 0.89 2 257 487 5f

405.13 0.71 2 314  16 5g

448.14 0.89 2  77  33 5h

404.13 0.75 2 108  11 5i

425.13 0.83 2  19  44 5j

469.12 0.83 2 468 423 5k

452.09 0.89 2  54  8 5l

455.14 0.91 2  11  77 5m

499.13 1.01 2  72 508 5n

454.15 0.93 2  42 221 5o

444.16 0.94 2 119  17 5p

445.16 0.94 2 224 123 5q

439.15 0.88 2  9  17 5r

431.14 0.85 2 144 177 5s

469.12 0.94 2 253 685 5t

407.09 0.76 2 264  56 5u

439.15 0.86 2 1336  385 5v

468.12 1.00 2  55 171 5w

439.13 0.82 2  20  3Method F:

Step 1:

Ketone F1 was converted to intermediate F2 using procedures similar tothose described in Method C steps 5-8.

Step 2:

To a mixture of compound F2 (350 mg, 0.853 mmol) in methanol (6 mL) andwater (2 mL) was added Zinc (278 mg, 4.27 mmol) and ammonium chloride(228 mg, 4.268 mmol). The resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was then filtered throughcelite and the filter cake was washed with excess of 1:1 mixture ofmethanol and dichloromethane. The filtrate was and concentrated and theproduct was used without further purification. m/z: 381.2

Step 3:

Amine F3 was converted to Example 6a following procedures similar tothose described in Method A steps 9 and 10.

TABLE 6 LCMS data Ex. t_(R) no. Example m/z (min) Conditions 6a

420.4 2.33 1

The example in Table 7 is made using procedures described in Method G.

TABLE 7 Ex. no. Example 7a

Method G:

Step 1:

To a solution of 2-(benzyloxy)acetic acid G1 (3.23 g, 19.5 mmol) in DCM(60 mL) was added EDCI (6.1 g, 29.2 mmol), followed by N,O-dimethylhydroxylamine hydrochloride (2.8 g, 29.2 mmol) and pyridine(10 mL). The mixture was stirred at 25° C. for 16 h, then washed with0.1 M aq. HCl, brine, dried (Na₂SO₄), and concentrated. The residue waspurified by silica gel chromatography (PE:EA=10:1) to afford G2.

Step 2:

Bromide G3 can be treated with nBuLi to afford the aryl lithiumintermediate in which G2 can be added to afford ketone G4.

Steps 3-7:

Ketone G4 can be converted to compound G9 following procedures similarto Method A steps 3-7.

Step 8.

Compound G9 can be treated with NBS and the like in the appropriatesolvent to afford bromide G10.

Step 9.

Treatment of G10 with BBr₃ in the appropriate solvent and temperaturecan provide compound G11.

Step 10:

Compound G11 can be treated under the appropriate conditions such asMitsunobu or BBr₃ to afford the dihydrobenzofuran G12.

Step 11.

Compound G12 can be converted to Example 7a following the proceduressimilar to those described in Method A steps 7 and 9-10.

LCMS Conditions

Conditions 1:

Column: Atlantis dCl8 (50×4.6 mm) 5.0 micron; Column temp: Ambient;Mobile phase: A: 0.1% Formic acid in water, B: 100% Acetonitrile;Gradient: From 0 to 3 min 95:5 to 5:95 (A:B), from 3-4 min 5:95 (A:B),from 4 to 4.5 min 5:95 to 95:5 (A:B), from 4.5 to 6 min 95:5 (A:B); Flowrate: 1.5 mL/min; UV detection: 215 nm; Mass spectrometer: Agilent 6130(Single) quadrupole.

Conditions 2:

Waters Acquity UPLC/MS, Electrospray positive ion mode; Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7 micron; Gradient elution 5:95 to100:0 MeCN (0.1% NH₄OH): water (0.1% NH₄OH) over 1.4 min 0.8 mL/min; UV:220 nm.

Assays

Protocols that used to determine the recited potency values for thecompounds of the invention are described below.

BACE1 HTRF FRET Assay

Reagents:

Na⁺-Acetate pH 5.0; 1% Brij-35; Glycerol; Dimethyl Sulfoxide (DMSO);Recombinant human soluble BACE1 catalytic domain (>95% pure); APPSwedish mutant peptide substrate (QSY7-APP^(swe)-Eu):QSY7-EISEVNLDAEFC-Europium-amide.

A homogeneous time-resolved FRET assay can be used to determine IC₅₀values for inhibitors of the soluble human BACE1 catalytic domain. Thisassay monitors the increase of 620 nm fluorescence that resulted fromBACE1 cleavage of an APPswedish APP^(swe) mutant peptide FRET substrate(QSY7-EISEVNLDAEFC-Europium-amide). This substrate contains anN-terminal QSY7 moiety that serves as a quencher of the C-terminalEuropium fluorophore (620 nm Em). In the absence of enzyme activity, 620nm fluorescence is low in the assay and increased linearly over 3 hoursin the presence of uninhibited BACE1 enzyme Inhibition of BACE1 cleavageof the QSY7-APP^(swe)-Eu substrate by inhibitors is manifested as asuppression of 620 nm fluorescence.

Varying concentrations of inhibitors at 3× the final desiredconcentration in a volume of 10 ul are preincubated with purified humanBACE1 catalytic domain (3 nM in 10 μl) for 30 minutes at 30° C. inreaction buffer containing 20 mM Na-Acetate pH 5.0, 10% glycerol, 0.1%Brij-35 and 7.5% DSMO. Reactions are initiated by addition of 10 μl of600 nM QSY7-APP^(swe)-Eu substrate (200 nM final) to give a finalreaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactionsare incubated at 30° C. for 1.5 hours. The 620 nm fluorescence is thenread on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50millisecond delay followed by a 400 millisecond acquisition time windowInhibitor IC₅₀ values are derived from non-linear regression analysis ofconcentration response curves. K_(i) values are then calculated fromIC₅₀ values using the Cheng-Prusoff equation using a previouslydetermined μm value of 8 μM for the QSY7-APP^(swe)-Eu substrate atBACE1.

BACE-2 Assay

Inhibitor IC_(50s) at purified human autoBACE-2 are determined in atime-resolved endpoint proteolysis assay that measures hydrolysis of theQSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay).BACE-mediated hydrolysis of this peptide results in an increase inrelative fluorescence (RFU) at 620 nm after excitation with 320 nm lightInhibitor compounds, prepared at 3× the desired final concentration in1×BACE assay buffer (20 mM sodium acetate pH 5.0, 10% glycerol, 0.1%Brij-35) supplemented with 7.5% DMSO are pre-incubated with an equalvolume of autoBACE-2 enzyme diluted in 1×BACE assay buffer (final enzymeconcentration 1 nM) in black 384-well NUNC plates for 30 minutes at 30°C. The assay is initiated by addition of an equal volume of theQSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration,K_(m)=8 μM for 4 μM for autoBACE-2) prepared in 1×BACE assay buffersupplemented with 7.5% DMSO and incubated for 90 minutes at 30° C. DMSOis present at 5% final concentration in the assay. Following laserexcitation of sample wells at 320 nm, the fluorescence signal at 620 nmis collected for 400 ms following a 50 μs delay on a RUBYstar HTRF platereader (BMG Labtechnologies). Raw RFU data is normalized to maximum (1.0nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC_(50s) aredetermined by nonlinear regression analysis (sigmoidal dose response,variable slope) of percent inhibition data with minimum and maximumvalues set to 0 and 100 percent respectively. Similar IC_(50s) areobtained when using raw RFU data. The K_(i) values are calculated fromthe IC₅₀ using the Cheng-Prusoff equation.

We claim:
 1. A compound, or a pharmaceutically acceptable salt thereof,said compound having the structural Formula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and-alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and-alkyl-cycloalkyl, is optionally substituted with one or more halogen;R² is selected from the group consisting of H, halogen, alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl,heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substitutedwith one or more halogen; R³ is selected from the group consisting of H,halogen, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, whereineach said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl isoptionally substituted with one or more halogen; s is 0 or 1; when s is0, then Y is absent and X is selected from the group consisting of—C(R^(1X))₂—, —O—, —S—, —S(O)—, and —S(O)₂—, and when s is 1, then X isselected from the group consisting of —C(R^(1X))₂—, —O—, —S—, —S(O)—,and —S(O)₂—, and Y is —C(R^(1Y))₂—, or, alternatively, when s is 1, thenX is —C(R^(1X))₂— and Y is selected from the group consisting of—C(R^(1Y))₂—, —O—, —S—, —S(O)—, and —S(O)₂—; each R^(1X) (when present)is independently selected from the group consisting of: H, halogen,alkyl, heteroalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, andcycloalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen; each R^(1Y) (when present) isindependently selected from the group consisting of: H, halogen, alkyl,heteroalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, andcycloalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen; ring A is selected from the groupconsisting of aryl and heteroaryl; m is 0 or more; each R^(A) (whenpresent) is independently selected from the group consisting of:halogen, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5A))₃, —N(R^(6A))₂, —OR^(6A),—SR^(6A), alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl ofR^(A) are each optionally independently unsubstituted or substitutedwith one or more groups independently selected from R⁸; n is 0 or 1;-L₁- represents a bond or a divalent moiety selected from the groupconsisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-,—NHC(O)—, —C(O)NH—, —C(S)NH—, —NHC(S)—, —NH—, —NHS(O)₂—, —S(O)₂NH—,—O—CH₂—, —CH₂—O—, —NHCH₂—, and —CH₂NH—; R^(L) is selected from the groupconsisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkylof R^(L) are each optionally unsubstituted or substituted with one ormore halogen; or, alternatively, R^(L) is a moiety having the formula

wherein q is 0 or 1; -L_(B)- (when present) is a divalent moietyselected from the group consisting of lower alkyl and lower heteroalkyl,wherein each said lower alkyl and lower heteroalkyl is optionallysubstituted with one or more halogen; ring B is selected from the groupconsisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl; p is 0 or more; and each R^(B)(when present) is independently selected from the group consisting of:halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃, —N(R^(6B))₂,—NR^(7B)C(O)R^(6B), —NR⁷S(O)₂R^(6B), —NR^(7B)S(O)₂N(NR^(6B))₂,—NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B), —C(O)R^(6B), —C(O)OR^(6B),—C(O)N(R^(6B))₂, —S(O)R^(6B), —S(O)₂R^(6B), —S(O)₂N(R^(6B))₂, —OR^(6B),—SR^(6B), alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein said alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,heteroaryl, and -alkyl-heteroaryl of R^(B) are each optionallyindependently unsubstituted or substituted with one or more groupsindependently selected from R⁹; each R^(5X), R^(5Y), R^(5A), R^(5B), andR^(5C) (when present) is independently selected from the groupconsisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, wherein each said alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl of R^(5X), R^(5Y), R^(5A), R^(5B), and R^(5C) isunsubstituted or substituted with one or more halogen; each R^(6X),R^(6Y), R^(6A) and R^(6C) (when present) is independently selected fromthe group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl,heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl,-alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(6X), R^(6Y), R^(6A)and R^(6C) is unsubstituted or substituted with one or more groupsindependently selected from halogen, alkyl, cycloalkyl, heteroalkyl,haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy; each R^(6B) (whenpresent) is independently selected from the group consisting of H,alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl, wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl,heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,heteroaryl, and -alkyl-heteroaryl of R^(6B) is unsubstituted orsubstituted with one or more groups independently selected from halogen,alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, andhaloalkoxy; each R^(7X), R^(7Y), R^(7A), R^(7B), and R^(7C) (whenpresent) is independently selected from the group consisting of H,alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl of R^(7X), R^(7Y), R^(7A), R^(7B), and R^(7C) isunsubstituted or substituted with one or more halogen; each R⁸ (whenpresent) is independently selected from the group consisting of halogen,lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, andlower heterocycloalkyl, wherein each said lower alkyl, lowerheteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkylof R⁸ is optionally substituted with halogen; and each R⁹ (when present)is independently selected from the group consisting of halogen, —OH,—CN, —SF₅, —OSF₅, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH,alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl,—O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl,—O-heterocycloalkyl and —O-alkyl-heterocycloalkyl, wherein each saidalkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.
 2. A compound of claim 1, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer,wherein: R¹ is methyl; R² is H; and R³ is H.
 3. A compound of claim 2,or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, wherein: s is 1; X is —O—; and Y is—C(R^(1Y))₂—, wherein each R^(1Y) is independently selected from thegroup consisting of H, lower alkyl, and lower heteroalkyl, wherein saidlower alkyl and lower heteroalkyl are each optionally independentlyunsubstituted or substituted with one or more halogen.
 4. A compound ofclaim 2, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, wherein: s is 0; Y is absent; and X isselected from the group consisting of —C(R^(1X))₂— and —O—, wherein eachR^(1X) (when present) is independently selected from the groupconsisting of H, halogen, lower alkyl, and lower heteroalkyl, whereinsaid lower alkyl and lower heteroalkyl are each optionally independentlyunsubstituted or substituted with one or more halogen.
 5. A compound ofclaim 2, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, wherein: s is 1; X is —C(R^(1X))₂—; andY is selected from the group consisting of —C(R^(1Y))₂— and —O—; R^(1X)is independently selected from the group consisting of H, halogen, loweralkyl, and lower heteroalkyl, wherein said lower alkyl and lowerheteroalkyl are each optionally independently unsubstituted orsubstituted with one or more halogen; and R^(1Y) is H.
 6. A compound ofclaim 2, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, wherein: ring A is selected from thegroup consisting of phenyl, pyridyl, thienyl, pyrimidinyl, andpyrazinyl; m is 0, 1, or 2; and each R^(A) (when present) isindependently selected from the group consisting of halogen, —CN, —SF₅,—NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—CH₂OCH₃, —S(CH₃), methyl, ethyl, cyclopropyl, —CH₂-cyclopropyl,—C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.
 7. A compound of claim6, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, wherein: R^(L) is selected from the groupconsisting of lower alkyl and lower heteroalkyl, wherein said loweralkyl and lower heteroalkyl of R^(L) are each optionally unsubstitutedor substituted with one or more halogen.
 8. A compound of claim 7, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, wherein: -L₁- is —C(O)NH—.
 9. A compound of claim 6,or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, wherein: R^(L) is a moiety having the formula

wherein: q is 1; -L_(B)- (when present) is a divalent moiety selectedfrom the group consisting of —CH₂—, —CF₂—, and —CH₂CH₂—; ring B isselected from the group consisting of isoxazolyl, oxadiazoyl, oxazolyl,phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl; p is 0 ormore; and each R^(B) group (when present) is independently selected fromthe group consisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.
 10. A compound of claim 9,or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, wherein: -L₁- is —C(O)NH—.
 11. A compound ofclaim 6, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, wherein: q is 0; and R^(L) is a moietyhaving the formula

wherein: ring B is selected from the group consisting of isoxazolyl,oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyrazolyl; p is 0 or more; and each R^(B) group (when present) isindependently selected from the group consisting of fluoro, chloro,bromo, —CN, —S(O)₂CH₃, —OCH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl, cyclopropyl, —CH₂-cyclopropyl,—CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,and —OCH₂CH₂F.
 12. A compound of claim 11, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer,wherein: -L₁- is —C(O)NH—.
 13. A compound of claim 1, or a tautomerthereof, or a pharmaceutically acceptable salt of said compound or saidtautomer, said compound selected from the group consisting of:


14. A pharmaceutical composition comprising a compound according toclaim 1, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, and a pharmaceutically acceptablecarrier or diluent.
 15. A method of treating a disease or pathology,wherein said disease or pathology is Alzheimer's disease, olfactoryimpairment associated with Alzheimer's disease, Down's syndrome,olfactory impairment associated with Down's syndrome, Parkinson'sdisease, olfactory impairment associated with Parkinson's disease,stroke, microgliosis brain inflammation, pre-senile dementia, seniledementia, progressive supranuclear palsy, cortical basal degeneration,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, mild cognitive impairment, glaucoma, amyloidosis, type IIdiabetes, diabetes-associated amyloidogenesis, scrapie, bovinespongiform encephalitis, traumatic brain injury, or Creutzfeld-Jakobdisease, said method comprising administering a compound according toclaim 1, or a tautomer thereof, or a pharmaceutically acceptable salt ofsaid compound or said tautomer, to a patient in need thereof in anamount effective to treat said disease or pathology.
 16. The method ofclaim 15, wherein disease or pathology is Alzheimer's disease.